A novel network pharmacology strategy to decode mechanism of Wuling Powder in treating liver cirrhosis.

BACKGROUND: Liver cirrhosis is a chronic liver disease with hepatocyte necrosis and lesion. As one of the TCM formulas Wuling Powder (WLP) is widely used in the treatment of liver cirrhosis. However, it's key functional components and action mechanism still remain unclear. We attempted to explore the Key Group of Effective Components (KGEC) of WLP in the treatment of Liver cirrhosis through integrative pharmacology combined with experiments. METHODS: The components and potential target genes of WLP were extracted from published databases. A novel node importance calculation model considering both node control force and node bridging force is designed to construct the Function Response Space (FRS) and obtain key effector proteins. The genetic knapsack algorithm was employed to select KGEC. The effectiveness and reliability of KGEC were evaluated at the functional level by using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the effectiveness and potential mechanism of KGEC were confirmed by CCK-8, qPCR and Western blot. RESULTS: 940 effective proteins were obtained in FRS. KEGG pathways and GO terms enrichments analysis suggested that effective proteins well reflect liver cirrhosis characteristics at the functional level. 29 components of WLP were defined as KGEC, which covered 100% of the targets of the effective proteins. Additionally, the pathways enriched for the KGEC targets accounted for 83.33% of the shared genes between the targets and the pathogenic genes enrichment pathways. Three components scopoletin, caryophyllene oxide, and hydroxyzinamic acid from KGEC were selected for in vivo verification. The qPCR results demonstrated that all three components significantly reduced the mRNA levels of COL1A1 in TGF-ß1-induced liver cirrhosis model. Furthermore, the Western blot assay indicated that these components acted synergistically to target the NF-κB, AMPK/p38, cAMP, and PI3K/AKT pathways, thus inhibiting the progression of liver cirrhosis. CONCLUSION: In summary, we have developed a new model that reveals the key components and potential mechanisms of WLP for the treatment of liver cirrhosis. This model provides a reference for the secondary development of WLP and offers a methodological strategy for studying TCM formulas.

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the destruction of synovial tissue and articular cartilage. Huangqi-Guizhi-Wuwu-Decoction (HGWD), a formula of Traditional Chinese Medicine (TCM), has shown promising clinical efficacy in the treatment of RA. However, the synergistic effects of key response components group (KRCG) in the treatment of RA have not been well studied. METHODS: The components and potential targets of HGWD were extracted from published databases. A novel node influence calculation model that considers both the node control force and node bridging force was designed to construct the core response space (CRS) and obtain key effector proteins. An increasing coverage coefficient (ICC) model was employed to select the KRCG. The effectiveness and potential mechanism of action of KRCG were confirmed using CCK-8, qPCR, and western blotting. RESULTS: A total of 796 key effector proteins were identified in CRS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses confirmed their effectiveness and reliability. In addition, 59 components were defined as KRCG, which contributed to 85.05% of the target coverage of effective proteins. Of these, 677 targets were considered key reaction proteins, and their enriched KEGG pathways accounted for 84.89% of the pathogenic genes and 87.94% of the target genes. Finally, four components (moupinamide, 6-Paradol, hydrocinnamic acid, and protocatechuic acid) were shown to inhibit the inflammatory response in RA by synergistically targeting the cAMP, PI3K-Akt, and HIF-1α pathways. CONCLUSIONS: We have introduced a novel model that aims to optimize and analyze the mechanisms behind herbal formulas. The model revealed the KRCG of HGWD for the treatment of RA and proposed that KRCG inhibits the inflammatory response by synergistically targeting cAMP, PI3K-Akt, and HIF-1α pathways. Overall, the novel model is plausible and reliable, offering a valuable reference for the secondary development of herbal formulas.

Extremely wideband low-RCS polarization conversion metasurface based on multivariate phase destructive interference.

In this paper, a polarization modulated metasurface to improve the magnitude and expand the bandwidth of radar cross section (RCS) reduction is presented. Two physical mechanisms are responsible for the reflection diffusion of the proposed metasurface. One is the functionality of controlling the spatial distribution of polarization response, and the other is the capability of spanning the entire 2π phase range by making full use of the variable sizes and height difference of unit cells to achieve superwideband phase cancellation. A 10 dB monostatic RCS reduction is obtained from 3.87 to 92.89 GHz (a ratio bandwidth of 24:1) for both polarizations under normal incidence by simulation, which is identical to experimental results and theoretical analysis. The proposed method for suppressing vector fields in an extremely wide band may hold promising potentials for suppression of acoustic, electromagnetic, optical and other elastic waves.

Kynurenic acid/GPR35 axis restricts NLRP3 inflammasome activation and exacerbates colitis in mice with social stress.

Psychological stress is well known to increase colitis susceptibility and promote relapse. Metabolic changes are commonly observed under psychological stress, but little is known how this relates to the progression of colitis. Here we show that kynurenic acid (KA) is an endogenous driver of social stress-exacerbated colitis via regulating the magnitude of NLRP3 inflammasome. Chronic social defeat stress (CSDS) in mice induced colonic accumulation of KA, and mice receiving KA during CSDS had defects in colonic NLRP3 inflammasome activation. Mechanistically, KA activated GPR35 signaling to induce autophagy-dependent degradation of NLRP3 in macrophages, thereby suppressing IL-1ß production. Socially defeated mice with KA treatment displayed enhanced vulnerability to subsequent dextran sulphate sodium (DSS)-induced colonic injury and inflammatory disturbance, and this effect was reversed by autophagic inhibition that blocked the NLRP3-suppressive effect of KA. Thus, our research describes a mechanism by which KA/GPR35 signaling represses adaptive NLRP3 inflammasome activation to increase colitis susceptibility and suggests a potential metabolic target for the intervention of stress-related colonic disorder.